Natural selection shaped the protective effect of the mtDNA lineage against obesity in Han Chinese populations.

Mitochondria play a key role in lipid metabolism, and mitochondrial DNA (mtDNA) mutations are thus considered to affect obesity susceptibility by altering oxidative phosphorylation and mitochondrial function. In this study, we investigated mtDNA variants that may affect obesity risk in 2,877 Han Chinese individuals from three independent populations. The association analysis of 16 basal mtDNA haplogroups with body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) revealed that only haplogroup M7 was significantly negatively correlated with all three adiposity-related anthropometric traits in the overall cohort (P=0.003 for BMI, P=1×10-5 for WC, P=0.005 for WHR), which was verified by the analysis of a single population, i.e., the Zhengzhou population. Furthermore, subhaplogroup analysis suggested that M7b1a1 was the most likely haplogroup associated with a decreased obesity risk, and the variation T12811C (causing Y159H in ND5) harbored in M7b1a1 may be the most likely candidate for altering mitochondrial function. Specifically, we found that proportionally more nonsynonymous mutations accumulated in M7b1a1 carriers, indicating that M7b1a1 was either under positive selection or subject to a relaxation of selective constraints. We also found that nuclear variants, especially in DACT2 and PIEZO1, may functionally interact with M7b1a1.

De Novo Dissecting the Three-Dimensional Facial Morphology of 2379 Han Chinese Individuals.

Phenotypic diversity, especially that of facial morphology, has not been fully investigated in the Han Chinese, which is the largest ethnic group in the world. In this study, we systematically analyzed a total of 14,838 facial traits representing 15 categories with both a large-scale three-dimensional (3D) manual landmarking database and computer-aided facial segmented phenotyping in 2379 Han Chinese individuals. Our results illustrate that homogeneous and heterogeneous facial morphological traits exist among Han Chinese populations across the three geographical regions: Zhengzhou, Taizhou, and Nanning. We identified 1560 shared features from extracted phenotypes, which characterized well the basic facial morphology of the Han Chinese. In particular, heterogeneous phenotypes showing population structures corresponded to geographical subpopulations. The greatest facial variation among these geographical populations was the angle of glabella, left subalare, and right cheilion (p = 3.4 × 10-161). Interestingly, we found that Han Chinese populations could be classified into northern Han, central Han, and southern Han at the phenotypic level, and the facial morphological variation pattern of central Han Chinese was between the typical differentiation of northern and southern Han Chinese. This result was highly consistent with the results revealed by the genetic data. These findings provide new insights into the analysis of multidimensional phenotypes as well as a valuable resource for further facial phenotype-genotype association studies in Han Chinese and East Asian populations. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-023-00109-x.

Analysis of blood methylation quantitative trait loci in East Asians reveals ancestry-specific impacts on complex traits.

Methylation quantitative trait loci (mQTLs) are essential for understanding the role of DNA methylation changes in genetic predisposition, yet they have not been fully characterized in East Asians (EAs). Here we identified mQTLs in whole blood from 3,523 Chinese individuals and replicated them in additional 1,858 Chinese individuals from two cohorts. Over 9% of mQTLs displayed specificity to EAs, facilitating the fine-mapping of EA-specific genetic associations, as shown for variants associated with height. Trans-mQTL hotspots revealed biological pathways contributing to EA-specific genetic associations, including an ERG-mediated 233 trans-mCpG network, implicated in hematopoietic cell differentiation, which likely reflects binding efficiency modulation of the ERG protein complex. More than 90% of mQTLs were shared between different blood cell lineages, with a smaller fraction of lineage-specific mQTLs displaying preferential hypomethylation in the respective lineages. Our study provides new insights into the mQTL landscape across genetic ancestries and their downstream effects on cellular processes and diseases/traits.

A comprehensive evaluation of the phenotype-first and data-driven approaches in analyzing facial morphological traits.

The phenotype-first approach (PFA) and data-driven approach (DDA) have both greatly facilitated anthropological studies and the mapping of trait-associated genes. However, the pros and cons of the two approaches are poorly understood. Here, we systematically evaluated the two approaches and analyzed 14,838 facial traits in 2,379 Han Chinese individuals. Interestingly, the PFA explained more facial variation than the DDA in the top 100 and 1,000 except in the top 10 phenotypes. Accordingly, the ratio of heterogeneous traits extracted from the PFA was much greater, while more homogenous traits were found using the DDA for different sex, age, and BMI groups. Notably, our results demonstrated that the sex factor accounted for 30% of phenotypic variation in all traits extracted. Furthermore, we linked DDA phenotypes to PFA phenotypes with explicit biological explanations. These findings provide new insights into the analysis of multidimensional phenotypes and expand the understanding of phenotyping approaches.

Metabolome subtyping reveals multi-omics characteristics and biological heterogeneity in major psychiatric disorders.

Growing evidence suggests that major psychiatric disorders (MPDs) share common etiologies and pathological processes. However, the diagnosis is currently based on descriptive symptoms, which ignores the underlying pathogenesis and hinders the development of clinical treatments. This highlights the urgency of characterizing molecular biomarkers and establishing objective diagnoses of MPDs. Here, we collected untargeted metabolomics, proteomics and DNA methylation data of 327 patients with MPDs, 131 individuals with genetic high risk and 146 healthy controls to explore the multi-omics characteristics of MPDs. First, differential metabolites (DMs) were identified and we classified MPD patients into 3 subtypes based on DMs. The subtypes showed distinct metabolomics, proteomics and DNA methylation signatures. Specifically, one subtype showed dysregulation of complement and coagulation proteins, while the DNA methylation showed abnormalities in chemical synapses and autophagy. Integrative analysis in metabolic pathways identified the important roles of the citrate cycle, sphingolipid metabolism and amino acid metabolism. Finally, we constructed prediction models based on the metabolites and proteomics that successfully captured the risks of MPD patients. Our study established molecular subtypes of MPDs and elucidated their biological heterogeneity through a multi-omics investigation. These results facilitate the understanding of pathological mechanisms and promote the diagnosis and prevention of MPDs.

Combined genome-wide association study of 136 quantitative ear morphology traits in multiple populations reveal 8 novel loci.

Human ear morphology, a complex anatomical structure represented by a multidimensional set of correlated and heritable phenotypes, has a poorly understood genetic architecture. In this study, we quantitatively assessed 136 ear morphology traits using deep learning analysis of digital face images in 14,921 individuals from five different cohorts in Europe, Asia, and Latin America. Through GWAS meta-analysis and C-GWASs, a recently introduced method to effectively combine GWASs of many traits, we identified 16 genetic loci involved in various ear phenotypes, eight of which have not been previously associated with human ear features. Our findings suggest that ear morphology shares genetic determinants with other surface ectoderm-derived traits such as facial variation, mono eyebrow, and male pattern baldness. Our results enhance the genetic understanding of human ear morphology and shed light on the shared genetic contributors of different surface ectoderm-derived phenotypes. Additionally, gene editing experiments in mice have demonstrated that knocking out the newly ear-associated gene (Intu) and a previously ear-associated gene (Tbx15) causes deviating mouse ear morphology.

Genetic variants underlying differences in facial morphology in East Asian and European populations.

Facial morphology-a conspicuous feature of human appearance-is highly heritable. Previous studies on the genetic basis of facial morphology were performed mainly in European-ancestry cohorts (EUR). Applying a data-driven phenotyping and multivariate genome-wide scanning protocol to a large collection of three-dimensional facial images of individuals with East Asian ancestry (EAS), we identified 244 variants in 166 loci (62 new) associated with typical-range facial variation. A newly proposed polygenic shape analysis indicates that the effects of the variants on facial shape in EAS can be generalized to EUR. Based on this, we further identified 13 variants related to differences between facial shape in EUR and EAS populations. Evolutionary analyses suggest that the difference in nose shape between EUR and EAS populations is caused by a directional selection, due mainly to a local adaptation in Europeans. Our results illustrate the underlying genetic basis for facial differences across populations.

Sex-Biased Population Admixture Mediated Subsistence Strategy Transition of Heishuiguo People in Han Dynasty Hexi Corridor.

The Hexi Corridor was an important arena for culture exchange and human migration between ancient China and Central and Western Asia. During the Han Dynasty (202 BCE-220 CE), subsistence strategy along the corridor shifted from pastoralism to a mixed pastoralist-agriculturalist economy. Yet the drivers of this transition remain poorly understood. In this study, we analyze the Y-chromosome and mtDNA of 31 Han Dynasty individuals from the Heishuiguo site, located in the center of the Hexi Corridor. A high-resolution analysis of 485 Y-SNPs and mitogenomes was performed, with the Heishuiguo population classified into Early Han and Late Han groups. It is revealed that (1) when dissecting genetic lineages, the Yellow River Basin origin haplogroups (i.e., Oα-M117, Oß-F46, Oγ-IMS-JST002611, and O2-P164+, M134-) reached relatively high frequencies for the paternal gene pools, while haplogroups of north East Asian origin (e.g., D4 and D5) dominated on the maternal side; (2) in interpopulation comparison using PCA and Fst heatmap, the Heishuiguo population shifted from Southern-Northern Han cline to Northern-Northwestern Han/Hui cline with time, indicating genetic admixture between Yellow River immigrants and natives. By comparison, in maternal mtDNA views, the Heishuiguo population was closely clustered with certain Mongolic-speaking and Northwestern Han populations and exhibited genetic continuity through the Han Dynasty, which suggests that Heishuiguo females originated from local or neighboring regions. Therefore, a sex-biased admixture pattern is observed in the Heishuiguo population. Additionally, genetic contour maps also reveal the same male-dominated migration from the East to Hexi Corridor during the Han Dynasty. This is also consistent with historical records, especially excavated bamboo slips. Combining historical records, archeological findings, stable isotope analysis, and paleoenvironmental studies, our uniparental genetic investigation on the Heishuiguo population reveals how male-dominated migration accompanied with lifestyle adjustments brought by these eastern groups may be the main factor affecting the subsistence strategy transition along the Han Dynasty Hexi Corridor.

Limb development genes underlie variation in human fingerprint patterns.

Fingerprints are of long-standing practical and cultural interest, but little is known about the mechanisms that underlie their variation. Using genome-wide scans in Han Chinese cohorts, we identified 18 loci associated with fingerprint type across the digits, including a genetic basis for the long-recognized "pattern-block" correlations among the middle three digits. In particular, we identified a variant near EVI1 that alters regulatory activity and established a role for EVI1 in dermatoglyph patterning in mice. Dynamic EVI1 expression during human development supports its role in shaping the limbs and digits, rather than influencing skin patterning directly. Trans-ethnic meta-analysis identified 43 fingerprint-associated loci, with nearby genes being strongly enriched for general limb development pathways. We also found that fingerprint patterns were genetically correlated with hand proportions. Taken together, these findings support the key role of limb development genes in influencing the outcome of fingerprint patterning.

A genome-wide association study of facial morphology identifies novel genetic loci in Han Chinese.

The human face is a heritable surface with many complex sensory organs. In recent years, many genetic loci associated with facial features have been reported in different populations, yet there is a lack of studies on the Han Chinese population. Here, we report a genome-wide association study of 3D normal human faces of 2,659 Han Chinese with autosegment phenotypes of facial morphology. We identify single-nucleotide polymorphisms (SNPs) encompassing four genomic regions showing significant associations with different facial regions, including SNPs in DENND1B associated with the chin, SNPs among PISRT1 associated with eyes, SNPs between DCHS2 and SFRP2 associated with the nose, and SNPs in VPS13B associated with the nose. We replicate 24 SNPs from previously reported genetic loci in different populations, whose candidate genes are DCHS2, SUPT3H, HOXD1, SOX9, PAX3, and EDAR. These results provide a more comprehensive understanding of the genetic basis of variation in human facial morphology.

Uniparental Genetic Analyses Reveal the Major Origin of Fujian Tanka from Ancient Indigenous Daic Populations.

The Fujian Tanka people are officially classified as a southern Han ethnic group, whereas they have customs similar to Daic and Austronesion people. Whether they originated in Han or Daic people, there is no consensus. Three hypotheses have been proposed to explain the origin of this group: (1) the Han Chinese origin, (2) the ancient Daic origin, (3) and the admixture between Daic and Han. This study addressed this issue by analyzing the paternal Y chromosome and maternal mtDNA variation of 62 Fujian Tanka and 25 neighboring Han in Fujian. The southern East Asian predominant haplogroups (e.g., Y-chromosome O1a1a-P203 and O1b1a1a-M95, and mtDNA F2a, M7c1, and F1a1) had relatively high frequencies in Tanka. The interpopulation comparison revealed that the Tanka have a closer affinity with Daic populations than with Han Chinese in paternal lineages but are closely clustered with southern Han populations such as Hakka and Chaoshanese in maternal lineages. Network and haplotype-sharing analyses also support the admixture hypothesis. The Fujian Tanka mainly originate from the ancient indigenous Daic people and have only limited gene flows from Han Chinese populations. Notably, the divergence time inferred by the Tanka-specific haplotypes indicates that the formation of Fujian Tanka was a least 1033.8-1050.6 years before present (the early Northern Song dynasty), indicating that they are an indigenous population, not late Daic migrants from southwestern China.

Genome-wide association studies and CRISPR/Cas9-mediated gene editing identify regulatory variants influencing eyebrow thickness in humans.

Hair plays an important role in primates and is clearly subject to adaptive selection. While humans have lost most facial hair, eyebrows are a notable exception. Eyebrow thickness is heritable and widely believed to be subject to sexual selection. Nevertheless, few genomic studies have explored its genetic basis. Here, we performed a genome-wide scan for eyebrow thickness in 2961 Han Chinese. We identified two new loci of genome-wide significance, at 3q26.33 near SOX2 (rs1345417: P = 6.51×10(-10)) and at 5q13.2 near FOXD1 (rs12651896: P = 1.73×10(-8)). We further replicated our findings in the Uyghurs, a population from China characterized by East Asian-European admixture (N = 721), the CANDELA cohort from five Latin American countries (N = 2301), and the Rotterdam Study cohort of Dutch Europeans (N = 4411). A meta-analysis combining the full GWAS results from the three cohorts of full or partial Asian descent (Han Chinese, Uyghur and Latin Americans, N = 5983) highlighted a third signal of genome-wide significance at 2q12.3 (rs1866188: P = 5.81×10(-11)) near EDAR. We performed fine-mapping and prioritized four variants for further experimental verification. CRISPR/Cas9-mediated gene editing provided evidence that rs1345417 and rs12651896 affect the transcriptional activity of the nearby SOX2 and FOXD1 genes, which are both involved in hair development. Finally, suitable statistical analyses revealed that none of the associated variants showed clear signals of selection in any of the populations tested. Contrary to popular speculation, we found no evidence that eyebrow thickness is subject to strong selective pressure.

Genome-wide variants of Eurasian facial shape differentiation and a prospective model of DNA based face prediction.

It is a long-standing question as to which genes define the characteristic facial features among different ethnic groups. In this study, we use Uyghurs, an ancient admixed population to query the genetic bases why Europeans and Han Chinese look different. Facial traits were analyzed based on high-dense 3D facial images; numerous biometric spaces were examined for divergent facial features between European and Han Chinese, ranging from inter-landmark distances to dense shape geometrics. Genome-wide association studies (GWAS) were conducted on a discovery panel of Uyghurs. Six significant loci were identified, four of which, rs1868752, rs118078182, rs60159418 at or near UBASH3B, COL23A1, PCDH7 and rs17868256 were replicated in independent cohorts of Uyghurs or Southern Han Chinese. A prospective model was also developed to predict 3D faces based on top GWAS signals and tested in hypothetic forensic scenarios.

Signatures of personality on dense 3D facial images.

It has long been speculated that cues on the human face exist that allow observers to make reliable judgments of others' personality traits. However, direct evidence of association between facial shapes and personality is missing from the current literature. This study assessed the personality attributes of 834 Han Chinese volunteers (405 males and 429 females), utilising the five-factor personality model ('Big Five'), and collected their neutral 3D facial images. Dense anatomical correspondence was established across the 3D facial images in order to allow high-dimensional quantitative analyses of the facial phenotypes. In this paper, we developed a Partial Least Squares (PLS) -based method. We used composite partial least squares component (CPSLC) to test association between the self-tested personality scores and the dense 3D facial image data, then used principal component analysis (PCA) for further validation. Among the five personality factors, agreeableness and conscientiousness in males and extraversion in females were significantly associated with specific facial patterns. The personality-related facial patterns were extracted and their effects were extrapolated on simulated 3D facial models.

Genetic variants associated with skin aging in the Chinese Han population.

BACKGROUND: The progression and manifestation of human skin aging has a strong genetic basis; however, most of the supporting evidence has been gathered in Caucasian populations. The genetic contribution to the variation in skin aging in non-Caucasian populations is poorly understood. OBJECTIVE: To investigate the genetic risk factors of relevance for skin aging in East Asians, we conducted the first candidate gene study for signs of skin aging in Han Chinese. METHODS: We collected skin aging and genotype data in 502 female Han Chinese from the Taizhou cohort. We evaluated skin aging by the validated skin aging score SCINEXA™. Confounding factors were assessed through a questionnaire. We obtained the genotype data for 21 candidate SNPs and for a further 509 SNPs from 16 related candidate genes. Associations were tested by linear and logistic regression analyses and adjusted for potential confounders. RESULTS: Our candidate study found a significant association between SNP rs2066853 in exon 10 of the aryl hydrocarbon receptor gene AHR and crow's feet. In addition, we found a significant association between SNP rs10733310 in intron 5 of BNC2 and pigment spots on the arms, and between SNP rs11979919, 3kb downstream of COL1A2, and laxity of eyelids. CONCLUSIONS: Our results identified genetic risk factors for signs of skin aging (pigmentation, wrinkles or laxity) in Han Chinese. We also found that the manifestation of skin aging is further modified by anatomical site. Together with previous work, our results also suggest that different genetic variants could be responsible for distinct skin aging signs characteristic of Caucasians compared to East Asians.